Adenovirus E1A binding to DCAF10 targets proteasomal degradation of RUVBL1/2 AAA+ ATPases required for quaternary assembly of multiprotein machines, innate immunity, and responses to metabolic stress
JOURNAL OF VIROLOGY(2023)
摘要
Adenovirus small e1a protein modifies host cell physiology to optimize virus replication. The N-terminal similar to 140 aa of e1a interacts with RB-family proteins to derepress dNTP and DNA synthesis and with EP300/CREBBP lysine acetyltransferases and EP400-TIP60 chromatin-modifying complexes to inhibit host anti-viral innate immune responses. However, the e1a N-terminal region activates a late host anti-viral response due to stabilization and activation of IRF3. The E1A C-terminal region counteracts IRF3 stabilization through interactions with three host nuclear proteins with seemingly unrelated functions. All three C-terminal interactions are required for e1a-association into a multi-protein complex with scaffold subunits of a CRL4 E3 ubiquitin ligase and DCAF10, a presumed specificity subunit. This e1a-DCAF10-CRL4 prevents IRF3 stabilization indirectly by targeting the essential AAA+ ATPases RUVBL1/2, subunits of several HSP90 co-chaperones required for quaternary assembly of cellular protein machines required for anti-viral defenses and responses to genotoxic and metabolic stress. IMPORTANCE Inactivation of EP300/CREBB paralogous cellular lysine acetyltransferases (KATs) during the early phase of infection is a consistent feature of DNA viruses. The cell responds by stabilizing transcription factor IRF3 which activates transcription of scores of interferon-stimulated genes (ISGs), inhibiting viral replication. Human respiratory adenoviruses counter this by assembling a CUL4-based ubiquitin ligase complex that polyubiquitinylates RUVBL1 and 2 inducing their proteasomal degradation. This inhibits accumulation of active IRF3 and the expression of anti-viral ISGs, allowing replication of the respiratory HAdVs in the face of inhibition of EP300/CBEBBP KAT activity by the N-terminal region of E1A.
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关键词
proteasomal degradation,metabolic stress
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